Derivatives of 1, 3-diaza-cycloalk-2-ene



United States Patent 3,332,948 DERIVATIVES 0F 1,3-DIAZA-CYCLOALK-2-ENEHerbert Morton Blatter, Millburn, N.J., assignor to Ciba Cor oration,New York, N.Y., a corporation of Delaware No Drawing. Filed June 20,1963, Ser. No. 289,394 The portion of the term of the patent subsequentto Jan. 12, 1982, has been disclaimed 11 Claims. (Cl. 260-251) in whichPh has the above-given meaning, Alk is alkyl, and the group of theformula --(C H is alkylene having from two to seven carbon atoms andseparating the two nitrogen atoms by two to four carbon atoms, and thetautomers thereof having a 1,3-diaza-cycloalk-3-ene ring system, andacid addition salts of such compounds.

The compounds of this invention have preferably the1,3-diaza-cycloalk-2-ene ring system, but may also be in N-Ph the formof the tautomeric 1,3-diaza-cycloalk-3-ene ring system.

A phenyl radial Ph is substituted by one or more than one hydroxyl,etherified hydroxyl, organic acyloxy, nitro, amino or N-substitutedamino group attached to any position available for substitution. Thegroup Ph represents primarily (hydroxy)-pheny1, (etherifiedhydroxy)phenyl, especially (lower alkoXy)-phenyl, in which lower alkoxyis methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy,n-pentyloxy, isopentyloxy and the like, as well as (loweralkenyloxy)-phenyl, in which lower alkenyloxy is allyloxy, methallyoxyand the like, (lower alkylenedioxy)-phenyl, in which lower alkylenedioxyis methylenedioxy and the like, (carbocyclic aryl-oxy)- phenyl, in whichcarbocyclic aryl-oxy is phenyloxy and the like, (carbocyclic aryl-loweralkoxy)-phenyl, in which carbocyclic aryl lower alkoxy is, for example,phenyl-lower alkyloxy, e.g. benzyloxy, Z-phenylethyloxy and the like,(carboxy-lower alkoxy)-phenyl, in which carboxy-lower alkoxy iscarboxymethoxy, 2-carboxyethoxy and the like, or [(carboxy-loweralkoxy)-lower alkoxy1-phenyl, in which (carboxy-lower alkoXy)-l0weralkoxy is (carbo methoxy) methoxy, (carbethoxy)- methoxy and the like,(organic acyl-oxy)-phenyl, such as (lower alkanoyloxy)-phenyl, in whichlower alkanoyloxy is acetyloxy, propionyloxy, pivalyloxy and the like,as well as (lower alkoxy-carbonyloxy)-phenyl, in which lower alkoxycarbonyloxy is methoxy carbonyloxy, ethoxycarbonyloxy and the like,(nitro)-phenyl, (amino)- phenyl, or (N-substituted)-phenyl, such as(N-monosubstituted amino)-phenyl, for example, (N-loweralkylamino)-phenyl, in which N-lower alkyl-amino is N- methylamino,N-ethylamino and the like, or (N-acylamino)-phenyl, for example,(N-lower alkanoyl-amino)- phenyl, in which N-lower alkanoyl-amino isN-acetylamino, N-propionylamino, N-pivalylamino and the like,

3,332,948 Patented July 25, 1967 "ice or (N,N-di-substitutedamino)-phenyl, for example, (N, N-di-lower alkylamino)-phenyl, in whichN,N-di-1ower alkyl-amino is N,N-dimethylamino, N,N-di-ethylamino and thelike.

The alkyl group Alk substituting the 2-position of the1,3-diazo-cycloalk-2-ene ring system, is primarily lower alkyl, havingfrom one to seven, preferably from one to four, carbon atoms, e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butylor tertiary butyl, as well as n-pentyl, isopentyl, n-hexyl, n-heptyl andthe like.

As mentioned above, the 1,3-diaza-cycloalk-2-ene portion has from fiveto seven ring members. The alkylene radical of the formula --(C,,Hhaving from two to seven carbon atoms, separates the two nitrogen atomsby two to four carbon atoms; its carbon atoms may be unsubstituted orcontain one or more than one lower alkyl group as substituents, e.g.methyl, ethyl, n-propyl, isopropyl and the like. The group of theformula (C H may, therefore, represent 1,2-ethylene, 1,3- propylene or1,4-butylene, as well as 1,2-propylene, 1,2- butylene, 2,3-butylene,1,3-butylene, 2-methyl-1,2-propylene, 1,4-pentylene and the like.

Salts of the compounds of this invention are acid addition salts, suchas the pharmaceutically acceptable, nontoxic acid addition salts withinorganic acids, e.g. hydrochloric, hydrobromic, nitric, sulfuric,phosphoric acids and the like, or with organic acids, such as organiccarboxylic acids, e.g. acetic, glycolic, maleic, hydroxymaleic, fumaric,malic, tartaric, citric, benzoic, salicylic, 4- aminosalicylicZ-acetoxy-benzoic, nicotinic, isonicotinic acid and the like, or organicsulfonic acids, e.g. methane sulfonic, ethane sulfonic, 2-hydroxy-ethanesulfonic, benzene sulfonic, toluene sulfonic, Z-naphthalene sulfonicacid and the like. Further acid addition salts are useful asintermediates, for example, in the manufacture of other acid additionsalts, such as pharmaceutically acceptable acid addition salts, or inthe purification of the free compounds, as well as for identificationand characterization purposes. Salts which are primarily used for thelatter are, for example, those with acidic organic nitro compounds, e.g.picric, picrolonic, flavianic acid and the like, or with metal complexacids, e.g. phosphotungsteio, phosphomolybdic, chloroplatinic, Reineckeacid and the like.

The compounds of this invention have diuretic and natriuretic propertiesand are, therefore, used as diuretic and natriuretic agents in thetreatment of excessive water and/or salt retention, due to heartinsufiiciency, kidney diseases and the like, or are useful intermediatesfor the preparation of the pharmacologically active compounds. Thelatter are remarkably free from undesired or secondary pharmacologicalproperties, such as excretion of potassium, or effects on the centralnervous system, such as stimulation and the like.

Particularly useful as diuretic and natriuretic agents or asintermediates for the preparation of the active compounds are thecompounds of the formula in which Ph is (hydroxy)-phenyl, (loweralkoxy)- phenyl, (phenyl-lower alkoxy)-phenyl, (nitro)-phenyl, or(amino)-phenyl, Alk is lower alkyl, and the group of the formula -(C His alkylene having from two to four carbon atoms and separating the twonitrogen atoms by two to three carbon atoms, as well as the tautomersthereof having the 1,3-diaza-cycloalk-3-ene ring system, and acidaddition salts, particularly pharmaceutically acceptable acid additionsalts, thereof. Such compounds are represented, for example, by those ofthe formula Alli IMG 0112 R do not react with the new compounds, such aswater,

gelatine, lactose, sucrose, Wheat starch, corn starch, stearic acid,magnesium stearate, calcium stearate, talc, vegetable oils, benzylalcohol, stearyl alcohol, gums, :ragacanth, propylene glycol,polyalkylene glycols, or any other pharmaceutically acceptable carriermaterial. The pharmaceutical preparations may be in solid form, for:xample, as capsules, tablets, dragees, suppositories and :he like, orin liquid form, for example, as solutions, susaensions, emulsions andthe like. If desired, they may :ontain auxiliary substances, such aspreserving, staailizing, wetting, emulsifying, coloring, flavoringagents 1nd the like, salts for varying the osmotic pressure, bufers,etc. They may also contain, in combination, other lseful substances.

The compounds of this invention are prepared accordng to known methods.A preferable procedure comprises 'eacting an N-Ph-alkylene-diaminecompound, in which h has the previously given meaning, and alkylenesepirates the two nitrogen atoms by two to four carbon ttoms, with analkanoic acid, having at least two carbon ttoms, a functional derivativethereof, or an equivalent tnalog thereof, and, if desired, converting asubstituent If the phenyl portion Ph of a resulting compound intoinother substituent, and/or, if desired, converting a reulting salt intothe free compound or into another salt, .nd/or, if desired, converting aresulting compound into salt thereof.

While an alkanoic acid having at least two carbon toms, such as acetic,propionic, butyric, isobutyric acid nd the like, may possibly be used inthe above ring losure reaction, it is advantageous to use a functionalerivative thereof, such as an ester, for example, a lower lkyl ester,e.g. methyl ester, ethyl ester and the like, aereof, or, moreparticularly, a tri-lower alkyl ortho ster, e.g. triethyl ortho esterand the like, of an alkanoic cid. Other functional derivatives of analkanoic acid re, for example, its amides, or the N-substituted imido)wer alkyl ethers thereof and the like, whereas an quivalent analog ofan alkanoic acid, capable of serving 1 the above reaction, is, forexample, a thio-amide theref, and the like.

The reaction of the diamine starting material with the ikanoic acid, orone of its functional derivatives, or an quivalent analog thereof, iscarried out in the absence f an additional solvent, particularly, if thereagent is multaneously a suitable diluent, such as a tri-lower alkylrtho-alkanoate, e.g. a triethyl ortho-lower alkanoate and to like. Ifdesired, the reaction mixture may be diluted ith a solvent, e.g.ethanol, n-propanol, diethyleneglycol imethylether, or any othersuitable diluent. The reaction preferably performed at an elevatedtemperature, it

:cessary, in a closed vessel under pressure, and/or, in ie atmosphere ofan inert gas, e.g. nitrogen.

The starting materials are known or may be prepared :cording to knownmethods; the asymmetrically substizted alkylenediamines' are preferablyprepared accordg to the Gabriel reaction.

The compounds of this invention may also be prepared by ring-closing anN-Ph-N-R -N'-R -alkylene diamine, in which Ph has the previously-givenmeaning, and alkylene separates the two nitrogen atoms by two to fourcarbon atoms, and in which one of the groups R and R is alkanoyl havingat least two carbon atoms, and the other is hydrogen or alkanoyl havingat least two carbon atoms, and, if desired, carrying out the optionalsteps.

The above ring-closing reaction is carried out according to knownmethods, for example, by heating the starting material, if necessary, inthe presence of a diluent, or by treating it with a suitable reagent,such as phosphorus pentachloride, calcium oxide and the like. Ifnecessary, it is performed in a closed vessel and/or in the atmosphereof an inert gas, e.g. nitrogen.

The starting material used in the above procedure is prepared accordingto known methods, for example, by reacting an N-Ph-alkylenediamine witha suitable functional derivative of an alkanoic acid having at least twocarbon atoms, such as a lower alkyl alkanoate, e.g. an ethyl loweralkanoate and the like, and isolating the desired N-lower alkanoylatedintermediate. Obviously, the starting materials may, therefore, beformed as intermediates in the previously-described reaction for theprep aration of the compounds of the invention without being isolated.

In the above procedures, certain substituents of the phenyl portion,such as amino, hydroxyl and the like,

, may have to be protected temporarily, for example, by

acylation, etherification and the like; furthermore, they may be presentin the form of functional groups, which are capable of being convertedinto such substituents. After the reaction, such groups are thenconverted or reconverted into the desired substituents.

Certain substituents attached to the phenyl portion Ph of a resultingcompound may be converted into other substituents. For example, a nitrogroup may be converted into amino according to known reduction methods,for example, by controlled treatment with hydrogen in the presence of asuitable catalyst, e.g. palladium on charcoal and the like. Furthermore,a lower alkoxy, e.g. methoxy and the like, group may be converted into afree hydroxyl group, for example, by acidic hydrolysis with hydrobromicacid in the presence of acetic acid, treatment with pyridinehydrochloride and the like. Furthermore, a group capable of being splitby hydrogenolysis, e.g. a benzyloxy group and the like, may be convertedinto hydroxyl by treatment with catalytically activated hydrogen.

A resulting acid addition salt may be converted into the free compoundby treatment with an alkaline reagent, such as a metal hydroxide, e.g.lithium hydroxide, sodium hydroxide, potassium hydroxide, calciumhydroxide, and the like, a metal carbonate, e.g. sodium, potassium orcalcium carbonate or hydrogen carbonate and the like, ammonia or anyother suitable reagent, such as a hydroxyl ion exchange preparation andthe like.

A resulting acid addition salt may be converted into another salt; forexample, an acid addition salt with an inorganic acid may be reactedwith a suitable metal, e.g. sodium, barium, silver and the like, salt ofan acid in the presence of a solvent, in which a resulting inorganiccompound is insoluble and is thus removed from the reaction medium. Theconversion of one salt into another may also be achieved by treatmentwith an anion exchange preparation.

A free compound may be converted into its acid addition salt by reactingit, preferably a solution thereof, with an acid or with an anionexchange preparation, and isolating the desired salt. The latter may beobtained in the form of a hydrate thereof or may contain solvent ofcrystallization.

The invention also comprises any modification of the process wherein acompound formed as an intermediate at any stage of the process of thisinvention is used as starting material and the remaining step(s) 0f ther process is (are) carried out, as well as any new inter-mediates.

In the process of this invention those starting materials are preferablyused which lead to the final products mentioned in the beginning as thepreferred embodiments of the invention.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade.

Example 1 A mixture of 1 g. of N (3-methoxy-phenyl)-ethylenediamine and5 ml. of triethyl orthopropionate is heated to 190-200 for three hourswhile maintaining an atmosphere of nitrogen and allowing the generatedethanol to evaporate. The excess of triethyl orthopropionate isdistilled off, and the residue is extracted with boiling penta-ne. Theorganic solution is decolorized with a charcoal preparation andevaporated to dryness. The resulting2-ethyl-1-(3methoxy-pheny1)-2-imidazoline of the formula for two hourson the steam bath, whereupon the mixture solidifies. It is diluted withwater; the organic material is extracted with diethyl ether. The organicsolution is cooled overnight to yield 90.0 g. of the crudeN-[2-(3-methoxyphenyl)-aminoethyl]-phthalimide, which upon extractionwith boiling cyclohexane and recrystallization, melts at 99-103".

A mixture of 35.0 g. of N-[2-(3-methoxy-phenyl) aminoethyll-phthalimideand 6.5 g. of 99-100 percent hydrazine hydrate in 500 ml. of 95 percentethanol is refluxed for twenty-one hours. The solid is filtered oif; thefiltrate is concentrated to yield an additional amountof the solidproduct. The combined crops are dissolved in a mixture of 200 ml. of 20percent aqueous sodium hydroxide and 200 ml. of water; the solution isextracted with methylene chloride, and the organic solution is driedover sodium sulfate and concentrated. The resulting crude N-(3-methoxy-phenyl)-ethylenediamine is extracted with boiling hexane andprecipitates upon cooling; it melts at Example? 7 A mixture of 10.0 g.of N-(4-nitro-phenyl) ethylenediamine and 55 ml. of triethylorthoacetate -is heated to 190-200 for thirty-five minutes, whilemaintaining an atmosphere of nitrogen and allowing the generated ethanolto evaporate. The excess of the triethyl acetate is distilled off, andthe solid residue is crystallized from acetone to yield 6.1 -g. of the2-methyl-1-(4-nitro-phenyl)- Z-imidazoline of the formula 6 ing theresulting N-[2 (4 nitro phenyl) aminoethyl]- phthalimide with hydrazinehydride; it melts at 152".

Example 3 A solution of 1.0 g. of 2-methyl-1-(4-nitro-phenyl)-2-imidazoline in ml. of ethanol is hydrogenated at atmospheric pressure inthe presence of 0.1 g. of a 10 percent palladium-on-charcoal catalyst.After the uptake of the theoretical amount of hydrogen (about one hour),the catalyst is filtered off, and the filtrate is evaporated to dryness.The crude 1-(4-amino-phenyl)-2-methyl-2-imidazoline of the formula(yield: 0.64 g.) is recrystallized from benzene after treatment with acharcoal preparation; M.-P. -166.

Example 4 treated with a concentrated solution of hydrogen chloride inisopropanol to yield 0.3 g. of the 2-ethyl-1-(3-methoxy-'phenyl)-1,4,5,6-tetrahydro-pyrimidine hydrobromide of the formulaCHM-CH3 rQ- ()OH ou 3 which melts at 155-156 after recrystallizationfrom a mixture of ethanol and diethylether.

The starting material used in the above procedure is prepared asfollows: A mixture of 134.0 g. of N-(Z-bromoethyD-phthalimide-and 123.0g. of m-anisidine is heated for three hours on the steam bath, and isthen diluted with water. The organic material is extracted with diethylether, from which a solid material precipitates; it is filtered off andtreated with 600 ml. of 1 N hydrochloric acid. The acid solution isfiltered, the filtrate is cooled, and the desired N-[3-(3 methoxyphenyl)-propylamine1- phthalimide precipitates; it melts at 97-100 afterrepeated recrystallization from a mixture of methanol and water.

A mixture of 1.0 g. of N-(3-methoxy-phenyl)-1,3-

propylamine1-phthalimide in 300 ml. of 95 percent ethavnol and 6.2 g. of99-100 percent hydrazine hydrate is re- A mixture of 1.0 g. of N-(3methoxy phenyl) 1,3 propylenediamine and 5 ml. of triethyl orthoacetateis heated to -200" for two hours while maintaining ar atmosphere ofnitrogen and allowing the generated etha 1101 to evaporate. The reactionmixture is worked-up as described in Example 4; the resulting 1,3-methoxyphenyl) -2-methyl-1,4,5,6-tetrahydropyrimidine hydrobromide ofthe formula OCHs (yield: 0.65 g.) melts at 184-186" afterrecrystallization from a mixture of ethanol and diethyl ether.

Other compounds prepared according to the above procedure by selectingthe appropriate starting materials are, for example,

Jpon treatment with an acid, e.g. hydrogen chloride, hylrogen bromide,maleic acid and the like, the above com- )ounds may be converted intotheir acid addition salts, e.g. iydrochlorides, hydrobromides, maleatesand the like. Fhe picrate of 2-ethyl-l-(3-methoxy-phenyl)-2-imid-azoineis prepared by treating a solution of the free comround in ethanol withpicric acid.

What is claimed is;

1. A member selected from the group consisting of a :ompound of theformula aiklk' N 1 which P11 is a member selected from the groupconisting of (hydroXy)-phenyl, (lower alkoxy)-phenyl, phenyl-loweralkoxy)-phenyl, (nitro)-phenyl, and (a- 1ino)-phenyl, Alk is loweralkyl, and the group of the ormula (C 'H is alkylene having from two toour carbon atoms and separating the two nitrogen atoms y two to threecarbon atoms, and a tautomer thereof hav- 1g the1,3-diaza-cycloalk-3-ene ring system and an acid ddition salt of Saidcompounds.

8 V 2. A- member selected from the group consisting of a compound of theformula Ha II-Ia R in which Alk is lower alkyl, and R is a memberselected from the group consisting of hydroxyl, lower alkoxy, nitro andamino and an acid addition salt thereof.

3. A member selected from the group consisting of2-ethyl-l-(3-methoXy-phenyl)-2-imidazoline and an acid addition saltthereof.

4. Z-ethyl-1-(3-methoxy-phenyl)-2-imidazoline hydrobromide 5. Z-methyl-1- (4-nitro-phenyl) -2imidazoline.

6. l-(4-amino-phenyl)lamethyl-Z-imidazoline.

7. A member selected from the group consisting of 2ethyl-1-(3-methoxy-phenyl)-1,4,5,6-tetrahydropyrim idine and an acidaddition salt thereof.

8. 2 ethyl-1-(3-rnethoxy-phenyl)-l,4,5,6-tetrahyropyrimidinehydrobromide.

9. A member selected from the group consisting of 1 (3-methoxy-phenyl)-2-methyl-1,4,5,6-tetrahydropyrimidine and an acid addition saltthereof.

10. 1 (3 methoxy-phenyl)-2-methyl-1,4,5,6-tetrahydropyrimidinehydrobromide.

11. A member selected from the group consisting of a compound of theformula References Cited UNITED STATES PATENTS 12/1964 Poppelsdeof260-251 1/1965 Blatter 260-250 OTHER REFERENCES Wertheim: Textbook ofOrganic Chemistry, pp. 763 764 (1945).

NICHOLAS S. RIZZO, Primary Examiner,

11. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THEFORMULA